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Yuka Takada - One of the best experts on this subject based on the ideXlab platform.
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discovery of a 1 methyl 3 4 dihydronaphthalene based sphingosine 1 phosphate s1p receptor agonist ceralifimod ono 4641 a s1p1 and s1p5 selective agonist for the treatment of autoimmune diseases
Journal of Medicinal Chemistry, 2017Co-Authors: Haruto Kurata, Kazuhiro Otsuki, Masakuni Kurono, Takaki Komiya, Hirotaka Mizuno, Hiroki Shioya, Hiroshi Hagiya, Kensuke Kusumi, Ryo Suzuki, Yuka TakadaAbstract:The discovery of 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylic acid 13n (ceralifimod, ONO-4641), a sphingosine-1-phosphate (S1P) receptor agonist selective for S1P1 and S1P5, is described. While it has been revealed that the modulation of the S1P1 receptor is an effective way to treat autoimmune diseases such as relapsing–remitting multiple sclerosis (RRMS), it was also reported that activation of the S1P3 receptor is implicated in some undesirable effects. We carried out a structure–activity relationship (SAR) study of hit compound 6 with an amino acid moiety in the hydrophilic head region. Following identification of a lead compound with a dihydronaphthalene central core by inducing conformational constraint, optimization of the lipophilic tail region led to the discovery of 13n as a clinical candidate that exhibited >30 000-fold selectivity for S1P1 over S1P3 and was potent in a Peripheral Lymphocyte lowering (PLL) test in mice (ED50 = 0.029 mg/...
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structure activity relationship studies of s1p agonists with a dihydronaphthalene scaffold
Bioorganic & Medicinal Chemistry Letters, 2012Co-Authors: Haruto Kurata, Kazuhiro Otsuki, Masakuni Kurono, Hirotaka Mizuno, Hiroki Shioya, Yuka Takada, Kensuke Kusumi, Ryo Suzuki, Natsuko Tokuda, Takaki KomiyaAbstract:Abstract Structure–activity relationship (SAR) of sphingosine-1-phosphate receptor agonists with a dihydronaphthalene scaffold was investigated. Compound 1 was modified to improve S1P1 agonistic activity and in vivo Peripheral Lymphocyte lowering (PLL) activity without impairing selectivity over S1P3 agonistic activity. A detailed SAR study of the terminal lipophilic part revealed that the introduction of substituents on the propylene linker and the terminal benzene ring influences in vitro and PLL activities. Compound 6n bearing a (S)-methyl group at the 2-position on the propylene linker and chlorine at the para-position on the terminal benzene ring showed potent hS1P1 agonistic activity with excellent selectivity over hS1P3 and in vivo PLL activity in mice.
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discovery of s1p agonists with a dihydronaphthalene scaffold
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Haruto Kurata, Kazuhiro Otsuki, Masakuni Kurono, Takaki Komiya, Hirotaka Mizuno, Hiroki Shioya, Yuka Takada, Kensuke Kusumi, Ryo Suzuki, Hiroshi HagiyaAbstract:Abstract Structure–activity relationship of sphingosine-1-phosphate receptor agonists was examined. Cinnamyl derivative 1 was modified to improve S1P1 agonistic activity as well as selectivity over S1P3 agonistic activity. Dihydronaphthalene derivative 10d was identified as a potent S1P1 receptor agonist with high selectivity against S1P3 and enhanced efficacy in lowering Peripheral Lymphocyte counts in mice.
Haruto Kurata - One of the best experts on this subject based on the ideXlab platform.
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discovery of a 1 methyl 3 4 dihydronaphthalene based sphingosine 1 phosphate s1p receptor agonist ceralifimod ono 4641 a s1p1 and s1p5 selective agonist for the treatment of autoimmune diseases
Journal of Medicinal Chemistry, 2017Co-Authors: Haruto Kurata, Kazuhiro Otsuki, Masakuni Kurono, Takaki Komiya, Hirotaka Mizuno, Hiroki Shioya, Hiroshi Hagiya, Kensuke Kusumi, Ryo Suzuki, Yuka TakadaAbstract:The discovery of 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylic acid 13n (ceralifimod, ONO-4641), a sphingosine-1-phosphate (S1P) receptor agonist selective for S1P1 and S1P5, is described. While it has been revealed that the modulation of the S1P1 receptor is an effective way to treat autoimmune diseases such as relapsing–remitting multiple sclerosis (RRMS), it was also reported that activation of the S1P3 receptor is implicated in some undesirable effects. We carried out a structure–activity relationship (SAR) study of hit compound 6 with an amino acid moiety in the hydrophilic head region. Following identification of a lead compound with a dihydronaphthalene central core by inducing conformational constraint, optimization of the lipophilic tail region led to the discovery of 13n as a clinical candidate that exhibited >30 000-fold selectivity for S1P1 over S1P3 and was potent in a Peripheral Lymphocyte lowering (PLL) test in mice (ED50 = 0.029 mg/...
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structure activity relationship studies of s1p agonists with a dihydronaphthalene scaffold
Bioorganic & Medicinal Chemistry Letters, 2012Co-Authors: Haruto Kurata, Kazuhiro Otsuki, Masakuni Kurono, Hirotaka Mizuno, Hiroki Shioya, Yuka Takada, Kensuke Kusumi, Ryo Suzuki, Natsuko Tokuda, Takaki KomiyaAbstract:Abstract Structure–activity relationship (SAR) of sphingosine-1-phosphate receptor agonists with a dihydronaphthalene scaffold was investigated. Compound 1 was modified to improve S1P1 agonistic activity and in vivo Peripheral Lymphocyte lowering (PLL) activity without impairing selectivity over S1P3 agonistic activity. A detailed SAR study of the terminal lipophilic part revealed that the introduction of substituents on the propylene linker and the terminal benzene ring influences in vitro and PLL activities. Compound 6n bearing a (S)-methyl group at the 2-position on the propylene linker and chlorine at the para-position on the terminal benzene ring showed potent hS1P1 agonistic activity with excellent selectivity over hS1P3 and in vivo PLL activity in mice.
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discovery of s1p agonists with a dihydronaphthalene scaffold
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Haruto Kurata, Kazuhiro Otsuki, Masakuni Kurono, Takaki Komiya, Hirotaka Mizuno, Hiroki Shioya, Yuka Takada, Kensuke Kusumi, Ryo Suzuki, Hiroshi HagiyaAbstract:Abstract Structure–activity relationship of sphingosine-1-phosphate receptor agonists was examined. Cinnamyl derivative 1 was modified to improve S1P1 agonistic activity as well as selectivity over S1P3 agonistic activity. Dihydronaphthalene derivative 10d was identified as a potent S1P1 receptor agonist with high selectivity against S1P3 and enhanced efficacy in lowering Peripheral Lymphocyte counts in mice.
Hu Yuanliang - One of the best experts on this subject based on the ideXlab platform.
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The effective comparison of five sulfated polysaccharides to stimulate chicken Peripheral Lymphocyte proliferation
Chinese journal of veterinary science, 2010Co-Authors: Guo Zhenhuan, Wang De-yun, Ma Xia, Hu Wei, Cao Yongping, Hu YuanliangAbstract:In order to select the sulfated polysaccharide(sPS) with the best immunoenhancement,the effects of sulfated astragalus polysaccharides(sAPS),sulfated epimedium polysaccharide(sEPS),sulfated lentinan(sLNT),sulfated Chinese angelica polysaccharide(sCAPS) and sulfated Lycium barbarum polysaccharide(sLBPS) on checken Peripheral Lymphocyte proliferation were compared in vitro.After the safe concentrations were tested,five sPSs within safe concentration scope were added into the cultivation system of chicken Peripheral Lymphocyte singly or synergistically with ConA.The Lymphocyte proliferations were determined by MTT method.The results showed that five sPSs at proper dose could stimulate the Lymphocyte proliferation singly or synergistically with ConA,and there was definite dose-effect relationship.sAPS60 had the best effect,and then sEPS5.
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Effects of Sulfated Polysaccharide Prescriptions on Chicken Splenic and Peripheral Lymphocyte Proliferation
Jiangsu Journal of Agricultural Sciences, 2010Co-Authors: Guo Zhenhuan, Ma Xia, Wang Zheci, Cao Baozhu, Qiu Jing, Fang Gang, Zhu Lin, Zhang Chunyuan, Wang Xingxiang, Hu YuanliangAbstract:To select the effective sulfated polysaccharide prescriptions(sPSPs) on enhancing the Lymphocyte proliferations,four sPSPs(sPSP1,sPSP2,sPSP3 and sPSP4) were prepared with sulfated astragalus polysaccharides(sAPS60),sulfated epimedium polysaccharide(sEPS5) and sulfated lentinan(sLNT2) selected in previous experiment.After the safe concentrations were tested,the four sPSPs were added into the cultivation system of chicken splenic or Peripheral Lymphocyte,singly or synergistically with PHA,LPS or ConA.After cultivated for 48 h,the Lymphocyte proliferations were determined by MTT method.The results showed that the four sPSPs could significantly stimulate the splenic Lymphocyte proliferation singly or synergistically with PHA and LPS,and stimulate Peripheral Lymphocyte proliferation synergistically with ConA.There were definite dose-effect relationships beween the concentrations of sPSPs and the stimulation effects.In comprehensive evaluation,sPSP1 and sPSP2 possessed the best efficacy.
Takaki Komiya - One of the best experts on this subject based on the ideXlab platform.
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discovery of a 1 methyl 3 4 dihydronaphthalene based sphingosine 1 phosphate s1p receptor agonist ceralifimod ono 4641 a s1p1 and s1p5 selective agonist for the treatment of autoimmune diseases
Journal of Medicinal Chemistry, 2017Co-Authors: Haruto Kurata, Kazuhiro Otsuki, Masakuni Kurono, Takaki Komiya, Hirotaka Mizuno, Hiroki Shioya, Hiroshi Hagiya, Kensuke Kusumi, Ryo Suzuki, Yuka TakadaAbstract:The discovery of 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylic acid 13n (ceralifimod, ONO-4641), a sphingosine-1-phosphate (S1P) receptor agonist selective for S1P1 and S1P5, is described. While it has been revealed that the modulation of the S1P1 receptor is an effective way to treat autoimmune diseases such as relapsing–remitting multiple sclerosis (RRMS), it was also reported that activation of the S1P3 receptor is implicated in some undesirable effects. We carried out a structure–activity relationship (SAR) study of hit compound 6 with an amino acid moiety in the hydrophilic head region. Following identification of a lead compound with a dihydronaphthalene central core by inducing conformational constraint, optimization of the lipophilic tail region led to the discovery of 13n as a clinical candidate that exhibited >30 000-fold selectivity for S1P1 over S1P3 and was potent in a Peripheral Lymphocyte lowering (PLL) test in mice (ED50 = 0.029 mg/...
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structure activity relationship studies of s1p agonists with a dihydronaphthalene scaffold
Bioorganic & Medicinal Chemistry Letters, 2012Co-Authors: Haruto Kurata, Kazuhiro Otsuki, Masakuni Kurono, Hirotaka Mizuno, Hiroki Shioya, Yuka Takada, Kensuke Kusumi, Ryo Suzuki, Natsuko Tokuda, Takaki KomiyaAbstract:Abstract Structure–activity relationship (SAR) of sphingosine-1-phosphate receptor agonists with a dihydronaphthalene scaffold was investigated. Compound 1 was modified to improve S1P1 agonistic activity and in vivo Peripheral Lymphocyte lowering (PLL) activity without impairing selectivity over S1P3 agonistic activity. A detailed SAR study of the terminal lipophilic part revealed that the introduction of substituents on the propylene linker and the terminal benzene ring influences in vitro and PLL activities. Compound 6n bearing a (S)-methyl group at the 2-position on the propylene linker and chlorine at the para-position on the terminal benzene ring showed potent hS1P1 agonistic activity with excellent selectivity over hS1P3 and in vivo PLL activity in mice.
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discovery of s1p agonists with a dihydronaphthalene scaffold
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Haruto Kurata, Kazuhiro Otsuki, Masakuni Kurono, Takaki Komiya, Hirotaka Mizuno, Hiroki Shioya, Yuka Takada, Kensuke Kusumi, Ryo Suzuki, Hiroshi HagiyaAbstract:Abstract Structure–activity relationship of sphingosine-1-phosphate receptor agonists was examined. Cinnamyl derivative 1 was modified to improve S1P1 agonistic activity as well as selectivity over S1P3 agonistic activity. Dihydronaphthalene derivative 10d was identified as a potent S1P1 receptor agonist with high selectivity against S1P3 and enhanced efficacy in lowering Peripheral Lymphocyte counts in mice.
Masakuni Kurono - One of the best experts on this subject based on the ideXlab platform.
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discovery of a 1 methyl 3 4 dihydronaphthalene based sphingosine 1 phosphate s1p receptor agonist ceralifimod ono 4641 a s1p1 and s1p5 selective agonist for the treatment of autoimmune diseases
Journal of Medicinal Chemistry, 2017Co-Authors: Haruto Kurata, Kazuhiro Otsuki, Masakuni Kurono, Takaki Komiya, Hirotaka Mizuno, Hiroki Shioya, Hiroshi Hagiya, Kensuke Kusumi, Ryo Suzuki, Yuka TakadaAbstract:The discovery of 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylic acid 13n (ceralifimod, ONO-4641), a sphingosine-1-phosphate (S1P) receptor agonist selective for S1P1 and S1P5, is described. While it has been revealed that the modulation of the S1P1 receptor is an effective way to treat autoimmune diseases such as relapsing–remitting multiple sclerosis (RRMS), it was also reported that activation of the S1P3 receptor is implicated in some undesirable effects. We carried out a structure–activity relationship (SAR) study of hit compound 6 with an amino acid moiety in the hydrophilic head region. Following identification of a lead compound with a dihydronaphthalene central core by inducing conformational constraint, optimization of the lipophilic tail region led to the discovery of 13n as a clinical candidate that exhibited >30 000-fold selectivity for S1P1 over S1P3 and was potent in a Peripheral Lymphocyte lowering (PLL) test in mice (ED50 = 0.029 mg/...
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structure activity relationship studies of s1p agonists with a dihydronaphthalene scaffold
Bioorganic & Medicinal Chemistry Letters, 2012Co-Authors: Haruto Kurata, Kazuhiro Otsuki, Masakuni Kurono, Hirotaka Mizuno, Hiroki Shioya, Yuka Takada, Kensuke Kusumi, Ryo Suzuki, Natsuko Tokuda, Takaki KomiyaAbstract:Abstract Structure–activity relationship (SAR) of sphingosine-1-phosphate receptor agonists with a dihydronaphthalene scaffold was investigated. Compound 1 was modified to improve S1P1 agonistic activity and in vivo Peripheral Lymphocyte lowering (PLL) activity without impairing selectivity over S1P3 agonistic activity. A detailed SAR study of the terminal lipophilic part revealed that the introduction of substituents on the propylene linker and the terminal benzene ring influences in vitro and PLL activities. Compound 6n bearing a (S)-methyl group at the 2-position on the propylene linker and chlorine at the para-position on the terminal benzene ring showed potent hS1P1 agonistic activity with excellent selectivity over hS1P3 and in vivo PLL activity in mice.
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discovery of s1p agonists with a dihydronaphthalene scaffold
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Haruto Kurata, Kazuhiro Otsuki, Masakuni Kurono, Takaki Komiya, Hirotaka Mizuno, Hiroki Shioya, Yuka Takada, Kensuke Kusumi, Ryo Suzuki, Hiroshi HagiyaAbstract:Abstract Structure–activity relationship of sphingosine-1-phosphate receptor agonists was examined. Cinnamyl derivative 1 was modified to improve S1P1 agonistic activity as well as selectivity over S1P3 agonistic activity. Dihydronaphthalene derivative 10d was identified as a potent S1P1 receptor agonist with high selectivity against S1P3 and enhanced efficacy in lowering Peripheral Lymphocyte counts in mice.